Blood includes erythrocytes, leukocytes and platelets as cell components. Among them, the leukocytes are classified into five categories: granulocytes (neutrophil, eosinophil and basophil), lymphocytes and monocytes. The neutrophils are the greatest number of cell types in human, and are well known to function on the front line of biological defense against bacterial infection, histological damage, and the like. The neutrophils are activated by bacterial cell components (e.g. lipopolysaccharide: LPS), bacteria-derived peptide, complement C5a, IL-8, and the like. The neutrophil is one of main ingredients of granulocytes in leucocytes, and when a foreign substance like bacteria enters a living body, the neutrophil migrates to its site and phagocytizes a foreign substance such as bacteria to generate active oxygen. Furthermore, the neutrophil plays an important role in release of bactericidal proteins such as lysozyme and defensin (degranulation) and elimination of foreign substances by actions of the proteins as well as various acidic hydrolase, or the like. However, if this active oxygen and the bactericidal proteins are excessively released outside the cells, they cause tissue damages, and optionally worsen an acute inflammation caused by entrance of foreign substances. Furthermore, in cases of particular diseases such as acute pulmonary disorder, acute respiratory distress syndrome and other neutrophil-related inflammations, this action of the neutrophil is known to have adverse effects on diseases.
Neutrophil elastase is a neutral protease having a molecular weight of about 30,000 and present in azurophil granule (lysosome). In a physiological state, in the neutrophil, the neutrophil elastase digests and degrades a phagocytized bacterium and foreign substance, and on the outside of the neutrophil, degrades elastin, collagen (types III and IV), fibronectin, immunoglobulin, blood coagulation factor XIII, etc. to regulate tissue biosynthesis. When the neutrophil elastase is excessively released and inhibitors such as α1-AT (α1-antitrypsin) are deficient, it may degrade even biological constituents and cause its own tissue damage. In inflammation, the neutrophil infiltrates into an inflammatory lesion, but conversely there is an aspect in which inflammation is caused by a substance produced by leucocyte like elastase. Recently, particularly in clinical sites, the kinetics of the neutrophil elastase and various diseases have attracted attentions. The neutrophil elastase has potent and broad degradation ability for proteins, and since it degrades particularly collagen, elastin, proteoglycan, etc. which are extracellular matrix components, it had been considered as one of factors of histological damages. Thus, medicines focusing to inhibitory effects of the neutrophil elastase are being developed. For example, there is a report that an H2 receptor antagonist, ranitidine hydrochloride (Name of drug: Zantac) decreases an intracellular Ca2+ concentration of the neutrophil and reduces release of the neutrophil elastase. In addition, sivelestat sodium (Name of drug: Elaspol) is a specific inhibitor for elastase released from the neutrophil out of the cell, and also a therapeutic agent which has a license to be applied to respiratory distress syndrome and acute pulmonary disorder in Japan. These drugs are not essentially drugs which inhibit activation of the neutrophil, but work on only one factor released by the activated neutrophil to inhibit its enzyme activity, and thus its anti-inflammatory action is expected.
Although there is a report about a substance which acts on a factor released an activated neutrophil and inhibits its activity as mentioned above, an inhibitory mechanism of the neutrophil is largely unknown. Particularly, for preventing runaway activation of the neutrophil in the circulation, the neutrophil should be kept in an inactive state. However, there has been no report about a factor capable of maintaining/regulating the neutrophil in an inactive state.
HRG (Histidine-rich glycoprotein) is a plasma protein with a molecular weight of about 80 kDa which was identified by Heimburger et al. in 1972. HRG is a high histidine-containing protein made up of a total of 507 amino acids in which 66 histidines are contained, and is mainly synthesized in a liver and contained in human plasma at a concentration as extremely high as about 100-150 μg/ml. HRG is known to be involved in regulation of a coagulation fibrinolysis system and control of angiogenesis (Non Patent Literature 1). Furthermore, a method for inhibiting angiogenesis by administration of a HRG polypeptide, and a pharmaceutical composition and a product which comprising the HRG polypeptide, an antibody and receptor binding to the HRG polypeptide, a HRG-deficient plasma and polynucleotide, a HRG polypeptide-coding vector and a host cell are disclosed (Patent Literature 1). Additionally, in relation to the field of angiogenesis, there is a disclosure relating to the use of a substantially-pure continuous polypeptide with an anti-angiogenesis activity containing a subfragment derived from a central area of the HRG (Patent Literature 2).
However, there has been no report about effects of the HRG on control of the neutrophil.